Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy

Abstract

In the recent years, the discovery of a series of mutations in patients with myeloid malignancies has provided insight into the pathogenesis of myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), and acute myeloid leukemia (AML). Among these alterations have been mutations in genes, such as IDH1/2, TET2, DNMT3A, and EZH2, which appear to affect DNA and/or histone lysine methylation. Large clinical correlative studies are beginning to decipher the clinical importance, prevalence, and potential prognostic significance of these mutations. Additionally, burgeoning insight into the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. DNA demethylating agents have been demonstrated to be clinically active in a subset of patients with MDS and AML and are used extensively. However, newer, more specific agents which alter DNA and histone modification are under preclinical study and development and are likely to expand our therapeutic options for these diseases in the near future. Here, we review the current understanding of the clinical importance of these newly discovered mutations in AML and MDS patients. We also discuss exciting developments in DNA methyltransferase inhibitor strategies and the prospect of novel histone lysine methyltransferase inhibitors.

Figure 1

Specific histone and DNA posttranslational modifications shown to be associated with mutations in epigenetic modifiers in hematologic malignancies. Only genetic alterations which have some evidence for resulting in a gain or loss of function are displayed here. Mutations which result in the acquisition of hyperactivation or new enzymatic activity are displayed on the left of nucleosome while mutations which have evidence as resulting in a loss of enzymatic function are displayed on the right (translocations known to directly affect histone posttranslational modifications are listed in Table 1). The majority of mutations in epigenetic modifiers in myeloid malignancies recently identified are known to affect posttranslational modifications on the N-terminal tail of histone H3 or at cytosines of DNA as displayed here. Currently, the function of DNMT3a mutations in AML has yet to be extensively clarified, particularly the recurrent R882 heterozygous mutations.